Positron emission tomography (PET) combined with computed tomography (CT) in an integrated PET/CT scanner offers a single-study, noninvasive technique for the diagnosis of coronary artery disease. PET/CT cardiac scans can provide complementary functional and anatomic assessments: PET can quantitate myocardial perfusion and metabolism offering insight into small vessel disease and tissue viability;while contrast enhanced CT angiography provides information on coronary anatomy and atherosclerotic burden. PET offers the potential for truly quantitative measurements, but this quantitation is confounded by (1) misaligned CT-based attenuation correction (CTAC) factors and (2) the limited sensitivity of PET imaging. Respiratory motion, cardiac motion, and/or patient movement cause misalignment between the CTAC image and the PET image. To reduce this misalignment, Aim 1 develops and evaluates CT acquisition protocols tailored for attenuation correction in cardiac PET imaging to improve qualitative and quantitative accuracy. The limited sensitivity of PET imaging results in noisy dynamic studies and requires image acquisitions over multiple respiratory and cardiac cycles. Aim 2 investigates methods to reduce these degradations with reconstruction methods tailored for myocardial blood flow estimation in cardiac PET imaging. This research plan complements a comprehensive training plan to facilitate Dr. Alessio's development as a bioimaging researcher and junior faculty member in the Department of Radiology at the University of Washington. Dr. Alessio's previous research has focused on statistical image processing and tomographic reconstruction. The proposed training plan including mentoring, biomedical coursework, and scholarly activities will allow him to transition into a biomedical role and solve pressing clinical problems in cardiac imaging. The mentors for this proposal represent several decades of experience - James Caldwell and James Bassingthwaighte for cardiovascular function and modeling and Thomas Lewellen and Paul Kinahan for nuclear medicine physics, image generation, and clinical protocol optimization. The University of Washington, with its internationally recognized programs in cardiovascular bioengineering, nuclear cardiology, and diagnostic physics, is an ideal environment for the development of an independent research career combining state of the art imaging techniques with clinical needs for the assessment of coronary disease. This development will occur while contributing solutions to what are widely recognized as the most important challenges in cardiac PET/CT imaging.